Xanthine oxidoreductase in digestive diseases: A context-dependent redox switch linking inflammation, metabolism and carcinogenesis

Xanthine oxidoreductase (XOR) is a molybdenum-containing enzyme that catalyzes the final steps of purine catabolism, generating uric acid and, under specific conditions, reactive oxygen species (ROS) and reactive nitrogen species. Due to its high expression in the liver and gastrointestinal tract, XOR has emerged as an important regulator of redox homeostasis, innate immunity and metabolic adaptation in digestive diseases. This review examines the role of XOR in hepatic disorders, intestinal ischemia-reperfusion (I/R) injury and inflammatory bowel disease (IBD), focusing on oxidative stress, tissue injury, host-microbiome interactions and carcinogenesis. Evidence indicates increased XOR activity in inflammatory and fibrotic liver diseases, where ROS generation contributes to hepatocellular damage, fibrosis and disease progression. In intestinal I/R injury, XOR links ATP depletion and hypoxanthine accumulation to reperfusion-associated oxidative stress, barrier dysfunction, bacterial translocation and systemic inflammation. In IBD, XOR participates in cytokine amplification, redox imbalance, thiopurine metabolism and inflammation-associated colorectal carcinogenesis. Emerging evidence also supports bidirectional interactions between XOR/urate metabolism and the gut microbiota, suggesting a broader role for XOR in regulating intestinal immune homeostasis. However, the biological significance of XOR is strongly context dependent. Whereas increased XOR activity promotes inflammatory tissue injury, advanced gastrointestinal malignancies are frequently characterized by reduced XOR expression, loss of cellular differentiation and enhanced de novo purine synthesis. Overall, XOR emerges as a central, but highly plastic, regulator at the interface between metabolism, inflammation and host-microbiome interactions in digestive diseases. Its clinical exploitation will depend on the ability to understand, rather than oversimplifying, this complexity.